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“Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh Jain, MD, USA
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“Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Dec 17, 2015

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Page 1: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

“Divide No More”

Cross Talk Between Pain, Anxiety, Depression & Insomnia

Rakesh Jain, MD, USA

Page 2: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Chronic Pain: Prevalence in the Community

1Blyth FM, et al. Pain. 2001;89(2-3):127-134; 2Elliott AM, et al. Lancet. 1999;354(9186):1248-1252; 3Gerdle B, et al. J Rheumatol. 2004;31(7): 1399-1406; 4OPENMinds. Pain in Europe–a public health priority. Mundipharma International Limited, 2011; 5Bouhassira D, et al. Pain. 2008;

136(3):380-387; 6Moulin DE, et al. Pain Res Manag. 2002;7(4):179-184; 7Johannes CB, et al. J Pain. 2010;11(11):1230-1239.

46.5%

53.7%

26% 30%

30.7%CHRONIC PAIN

31.7%

M:17.1%

F:20%

M:27%

F:31%

Page 3: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

DO PAIN CONDITIONS & PSYCHIATRIC DISORDERS REALLY INTERSECT?

Page 4: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

*Data show odds ratio with 95% confidence intervals.

World Mental Health Survey (N=42,249)

0

1

2

3

4

5

6

Asthma HTN Arthritis Heart Disease Back/Neck Pain Chronic Headache

Multiple Pains

Odd

s Rati

o*

P<.05 for all comparisons vs. persons with neither depression nor anxiety

Depression and anxiety

DepressionAnxiety

HTN=hypertension.Scott KM et al. J Affect Disord. 2007;103:113-120.

Anxiety & Depression are HIGHLY Associated with Physical Conditions and Symptoms

Page 5: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Divided No More - Insomnia: Emotional and Cognitive Sequelae

Leger D, et al. Curr Med Res Opin. 2005;21(11):1785-1792

Insomniacs (%)

Insomnia significantly impacts Anxiety and activities of daily living

N=570 individuals >18 years, reporting insomnia in the past 12 months.

Page 6: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Adjusted odds ratio (adjusted for age, race, sex & educational status)

Weighted 12-month adjusted odds ratio of association between severe headaches or migraine with mental

disorders

***

*p<0.05

Pain Condition (Headaches) and Psychiatric Disorders

Kalaydjian A, Merikangas A. Psychosom Med 2008;70(7):773-780.

Major De-pression

Panic D/O Generalized Anxiety D/O

1.0 1.0 1.0

2.84

3.293.03

Ad

just

ed o

dd

s ra

tio

n=15,330 - without headaches

n= 3,045 - with headaches

Page 7: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

No Pain n=50

Chronic Pain n=40

2.0

4.6

3.1

5.4HADS-depression scoreHADS-anxiety score

Mea

n sc

ore

*p<0.05

• 3 years later – 45% had chronic pain

• 3 years after accident – 4.4% developed PTSD

• 10%+ developed subsyndromal PTSD

• all but one patient with PTSD (full or subsyndromic) had chronic pain

**

Chronic Pain After Accidental Injury & Its Relationship To Anxiety / Depression

Jenewein J, et al. J Psychosom Res. 2009;66(2):119-126.

Page 8: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

“Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in FM

Arnold LM, et al. J Clin Psychiatry. 2006;67(8):1219-1225.

FibromyalgiaAny

Anxiety Disorder

6.7

Eating Disorder

2.4

Substance Use

Disorder 3.3

Major Depressi

on2.7

N = 108 with fibromyalgia, 228 without fibromyalgia

Page 9: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Mild Moderate Severe

6.1

7.9

10.3

6.7

8.9

11.0HADS-depression scoreHADS-anxiety score

*

BPI – DPN Average Pain Severity

Sco

re

** *

HADS = Hospital Anxiety and Depression Scale; BPI = Brief Pain Inventory

N = 255

DPNP Patients – Relationship Between Pain & Mental Disorders

Gore M, et al. J Pain Symptom Manage. 2005;30(4):374-385.

*p<0.05

Page 10: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Is Pain Affected by the Co-occurrence of Anxiety and/or Depression?

Bair MJ, et.al. Psychosom Med. 2008;70(8):890-897.

Bri

ef P

ain

In

ven

tory

Pai

n S

core

(m

ean

) ra

ng

e :

0-10

Pain + Depression (n=98)

1

2

4

6

5

3

8

7

Pain Severity Pain Interference

Pain only (n=271)

Pain + Anxiety (n=15)

Pain + Anxiety + Depression (n=116)

*p<0.001

**

* *

**

Page 11: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Temporal Sequence of Anxiety Disorders Onset and Co-morbid Physical Conditions

72.0

69.7

61.8

58.8

73.6

73.4

61.8

63.7

64.3

Hypertension

Cardiac diseases

Respiratory diseases

Gastrointestinal diseases

Diabetes

Arthritic conditions

Allergic conditions

Migraine headaches

Thyroid diseases

Comorbid Cases Where Anxiety Disorder Preceded Physical Condition, % (95% CI)

CI=confidence interval.Sareen J et al. Arch Intern Med. 2006;166:2109-2116.

Page 12: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain?

11.4

2.6

score 0-4 score 5-7 score 8-21

Gupta A et al. Rheumatology 2007;46:666-71.

1

1.8

2.9

score 0-2 score 3-5 score 6-20

Anxiety (HAD Anxiety sub-score) Depression (HAD Depression sub-score)

Sleep (Sleep Problem Scale)

15-month prospective study, 3171 followed, 324 developed chronic widespread pain

Odds

ratio

Odds ratio

Odds

ratio

Page 13: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

WHAT IS THE NEUROBIOLOGY OF PAIN – MIND REALTIONSHIP?

Page 14: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain

Adapted from Giordano J. Pain Physician 2005;8:277-90

Slow, unmyelinated C-fibers

Somatosensory cortex

Thalamus

Limbic system

CerebrumBrainstem

Spinal cordSpinothalamic tract

Dorsalganglion

Afferent nerve fiber

Fast, myelinated

A-fibers

Page 15: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

A Closer Look at Shared Anatomy: Complex Circuits Involve Sensory, Cognitive and Emotional Regions

Apkarian AV et al. Eur J Pain 2005;9:463-84

SECmodel

• Sensory• Emotional• Cognitive

SC

E

Page 16: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Giordano J. Pain Physician 2005;8:277-290

CORTICO-LIMBIC INPUT

PAGOPIOIDS

RMCNE

DLF

NRM5-HT

SPINAL INTER-

NEURON

MIDBRAINBRAINSTREAM

Primary nociceptiv

e afferents

(+)

(+)

(-)

(+)

(+)

(+)

(+)

(-)(-)

(-)

PSTT

GABAINTER-

NEURON

Many Neurotransmitters Are Shared by Pain & Anxiety

5-HT=5-hydroxytryptamine; DLF=dorolateral funiculus; NRM=nucleus raphe mangus; RMC=magnocellular nuclei; PAG=periaqueductal grey substance; PSTT=paleospinothalic tract.

Page 17: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Neuroendocrine and Neuroimmune Dysregulation in Pain Syndromes

1 Raison CL et al. Trends Immunol 2006;27:24-31; 2 Nestler EJ et al. Neuron 2002;34:13-25; 3 Blackburn-Munro G et al. J Neuroendocrinol 2001;13:1009-23

Red = inhibitory pathway

Green = stimulatory pathway

Page 18: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Pain is a Mind-Body Disorder: Anxiety/ Depression/Insomnia is a Mind-Body Disorder

Jain R, et al, Diabetes Report Curr Diab Rep 2011;11:275–284

Page 19: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Back Pain: Gray Matter Atrophy in Areas Involved with Cognition and Emotional Regulation

Apkarian AV et.al. J Neurosci 2004;24(46):10410-10415

Patients with chronic back pain (CBP) had 5-11% less whole brain gray matter, equivalent to 10-20 years of normal aging

Page 20: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Good News – Yes! Improved Structural & Cognitive Functioning Post Treatment

Seminowitz DA, et al. J Neurosci 2011;31(20):7540-7550

Page 21: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Toxic Triple Threat

PAIN

DEPRESSION ANXIETY

Page 22: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

COGNITIVE BEHAVIORAL THERAPY Is It Effective In Chronic Pain?

It is with Depression and Anxiety and Insomnia

Page 23: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Does CBT Impact the Brain of a Chronic Pain Patient? Answer: Yes

DFPFC = Dorsolateral Pre Frontal Cortex, SMA = Sensory Motor Association Cortex. Seminowicz DA, et al. J Pain. 2013;14(12):1573-1584.

Voxel-based morphometry to compare anatomic MRI scans of 13 patients with mixed chronic pain types before and after an 11-week CBT treatment

and to 13 healthy control participants

Page 24: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Not Only That, CBT Also Reduces Catastrophizing and This Has Brain Correlates

Seminowicz DA, et al. J Pain. 2013;14(12):1573-1584.

IFG, inferior frontal gyrus; S1, primary somatosensory cortex; S2, secondary somatosensory cortex.

Page 25: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

HOW DOES INSOMNIA FIT IN THE CROSS TALK BETWEEN GAD AND CHRONIC PAIN ?

Page 26: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Neural Sleep-Promoting Pathways

Complex interactions among the nuclei in

the hypothalamus and brainstem determine the onset of sleep

Saper CB, et al. Nature. 2005;437(7063):1257-1263

Thalamus

PeF

vPAG (DA)VLPO (GABA, Ga)

TMN (H)Raphe (5-HT)

PPT (ACh)

LDT (ACh)

LC(NA)SCN

Brainstem

CerebellumMedulla

HypothalamusPons

PeF=perifornical regionVLPO=ventrolateral preoptic nucleus.

Page 27: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Nofzinger EA et al. Am J Psychiatry. 2004;161:2126-2129.

ARAS

Thalamus

Mesial temporal cortex

Insular cortex

ARAS

Mesial temporal cortex

Hypothalamus

Cingulate cortex

Hypothalamus

Arousal systems in insomnia patients that do not deactivate from waking to sleep

ARAS

ARAS=ascending reticular activating system.

Some Brain Regions Do Not “Switch Off” in Insomnia Patients

Page 28: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Insomnia patients have lower metabolism during waking in prefrontal cortex, ARAS, and thalamus, compared with healthy controls

Nofzinger EA et al. Am J Psychiatry. 2004;161:2126-2129.

PFC

Th

ARAS

PFC=prefrontal cortex; Th=thalamus; ARAS=ascending reticular activating system

Daytime Fatigue in Insomnia Patients Is Related to Relative Hypometabolism in Frontal Areas

Page 29: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Decreased Hippocampal volume in Insomnia is associated with Cognitive Impairment and Hyper-arousal

0 5 10 15 20 25

Higher values on the arousal index correspond to poor sleep quality. Left or right hippocampal volume was negatively correlated with the insomnia duration (left: r=-0.872, p<0.001; right: r=-0.868, p<0.001) (A) and with the arousal index in nighttime polysomnography (left: r=-0.435, p=0.045; right: r=-0.409, p=0.026) (B).

Noh et al, 2012, J Clin Neurol ; 8:130-138.

4500 Right

hippocampus Left

hippocampus 4000

Hip

pocam

pal volu

me (

mm

3 )

3500

3000

2500

2000 0 10 20 30

40 B Arousal index

(/hr)

4500 Right hippocampus Left hippocampus

4000

Hip

pocam

pal volu

me (

mm

3 )

3500

3000

2500

2000

A Duration of insomnia (year)

n=20

Page 30: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

CLINICAL CONSIDERATIONS

Page 31: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Recognition of neuropathic pain may be challenging for many clinicians:

Proportion of physicians finding it difficult to recognize NeP

0 10 20 30 40 50 60 70

2010 4030 500 60 70

General practitioner

Oncologist

Rheumatologist

HIV specialist

Neurologist

Endocrinologist

Pain specialist

Area of expertise

Percentage of physicians

Page 32: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Prevalence of Neuropathic Pain

Painful Diabetic Neuropathy (PDN)• Painful diabetic neuropathy occurs in up to 26% of all people with

diabetes1

• Diabetes is a significant healthcare problem in Africa and the Eastern Mediterranean / Middle East regions, affecting:

– An estimated 35 million people (5% of the adult population) in 20072

– A predicted 63 million people (6% of the adult population) by 20252

Low back pain• In patients with chronic low back pain, 37% may have predominantly

neuropathic pain3

Postherpetic Neuralgia (PHN)• Neuropathic pain affects 25-50% of people over 50 who have had

herpes zoster4

1. Davies M, et al. Diabetes Care. 2006;29:1518-22.2. International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels (Belgium); 2006.3. Freynhagen R, et al. Curr Med Res Opin. 2006;22:1911-20. 4. Schmader KE. Clin J Pain 2002; 18(6):350-54.

Page 33: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

And Furthermore...The SEC Model Integrates Non-Pharmacological and Pharmacological Rx Of Pain

SensoryCognitive

Emotional

Non-pharmacological

Non-pharmacological

Non-pharmacological

Pharmacological

Pharmacological PharmacologicalSEC = Sensory, Emotional, Cognitive

Page 34: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

3 weeks of multidisciplinary treatment consisted of education, stretching, CBT, relaxation training and aerobic exercise

Adapted from: Bonifazi M et al. Psychoneuroendocrinology 2006;31:1076-86.

Multidisciplinary Treatment: Impact on Improvement and HPA Changes

HPA=hypothalamic-pituitary-adrenal; CBT=cognitive behavioral therapy; CES-D=Center for Epidemologic Studies Depression Rating Scale

Before admission and treatmentBefore treatment After treatment

TenderPoints

Score Area Score

64.1

57.3

22.4

5.5

48.9

38

13.3

63.1

24.9

69

13.5

13.3

Positive VAS % of Pain CES-D

*

*

*

*

*p<0.05

N=12

Salivary cortisol concentration

Pre-treatmentPost-treatment

9

8

7

6

5

4

3

2

0800 1000 1200 1400 1600 1800 2000 2200

Time of sample

ng

/ml

Page 35: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Pharmacological Treatment Options for Anxiety Disorders

Benzodi-azepines SSRIs

α2δ ligandsSNRIs

Page 36: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Anxiety, Stress, Neuroendocrine, and Immune Dysfunction as Potential Pain Mediators

Yunus MB. Semin Arthritis Rheum 2007;36:339-56

Genetic predisposition

Neuroendocrine- immune

dysfunction

Central sensitivity syndromes

ANS dysfunctionPoor sleep

TraumaPsychological factors, stress

Infections, Inflammation

Neonatal, Childhood

trauma

Otherfactors

Hyperexcitement of central neurons Environmental,

ChemicalCentral

sensitization

Central sensitization

Other mechanisms

Page 37: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Layering of Therapeutic Options in Chronic Pain! – All Options are on the Table

Page 38: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Successful Management of Neuropathic Painhas a Positive Impact for the Patient

The earlier a diagnosis is made, the moreopportunities there are to improve patient outcomes.

Treatment of underlying conditions and of pain symptoms

Assessment/ Diagnosis

Improvedquality ofsleep

Improved overall quality of life

Improved physical functioning

Improved psychological state

Reduced pain

38

Page 39: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

Effects of Chronic Pain on the Patient

MoodsDepressionAnxietyAngerIrritability

Social FunctioningDiminished social relationships (family/friends)Decreased sexual function/intimacyDecreased recreational and social activities

Societal ConsequencesHealth care utilizationDisabilityLoss of work daysSubstance abuse

Physical FunctioningMobilitySleep disturbancesFatigueLoss of appetite

Ashburn and Staats. Lancet, 1999;353(9167):1865-9 39

Page 40: “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia “Divide No More” Cross Talk Between Pain, Anxiety, Depression & Insomnia Rakesh.

In Conclusion: The Cross Talk Between Pain/Anxiety/ Depression/Insomnia Needs to be Addressed

Optimum would be early, full, and sustained control over ALL symptoms, regardless of our specialty!

Pain

Sleep

Fatigue

Anxiety

Mood